Cancer is one of the most fateful diseases that threaten human beings' lives and health. In various diseases, the mortality of malignant tumor is among the second place, just behind cardiovascular and cerebrovascular diseases. Although medical technologies are developing constantly, and the therapeutic means for cancer in which surgery as well as radiochemotherapy and chemoradiotherapy are selected as the major approaches have made great progress, however, cancer is still very difficult to treat since the pathogenesis thereof is complex. Consequently, finding the small molecule anticancer agents with high efficacy and low toxicity is always the hot spot and difficulty in the realm of current cancer treatment.
Hepatocyte growth factor receptor (c-Met) is a receptor type tyrosine kinase, which is encoded by Met proto-oncogene (Bottaro D P et al. Science 1991, 251(4995):802˜804) and generally includes 190-kDa heterodimer (a 50-kDa α-chain and a 145-kDa β-chain linked by bisulfide) transmembrane tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 1987, 84:6379˜6383). C-Met has the biological effect of transducting hepatocyte growth factor (HGF). As the ligand of c-Met, HGF is also known as scatter factor (SF), which is a heterodimer protein secreted by cells originated from mesoderm. C-Met and HGF are needed by the growth of normal mammals, expressed in the many tissues, and are shown to be important in cell migration, cellular proliferation and survival, morphogenesis and differentiation, as well as the organization of 3-dimensional tubiform structure (e.g. the formation of nephridia cells and glands) (James G. Christensen, et al., Cancer Letters, 2005, 225: 1˜26). HGF induces the mitogenesia of epithelial cells, stimulates cell mobility and promotes the penetration of matrix. Besides the effect on epithelial cells, HGF/SF has also been reported to be an angiogenesis factor, and the c-Met signals in endothelial cells can induce many of the cellular responses required by angiogenesis (proliferation, mobility, penetration).
It is known that c-Met signal pathway plays an important role in the aspects of transformation, proliferation, survival, infiltration, and metastasis of cells. C-Met signal transduction pathway is closely related to tumorigenesis. It is shown that c-Met and the ligand HGF are overexpressed in many types of human cancers, and participated in oncogenesis. High levels of HGF and/or c-Met are observed in tumors of liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate and gall bladder, myeloma as well as many other tumors. Many studies have found that the expression of c-Met and/or HGF are correlated to the state of progression of the above mentioned different kinds of cancers (Fabiola et al, European Journal of Cancer, 2010, 46:12601270).
Therefore, it can be seen that c-Met tyrosine kinase and the downstream regulated signal pathways thereof are important to the proliferation, differentiation and metastasis processes of tumor cells. Accordingly, the blockade of these signal pathways is considered to be an active means for treating cancers.
In summary, c-Met is considered to be an efficacious target for treating cancers. Inhibition on the activity of c-Met can effectively control the growth and metastasis of tumor cells, and enhance the sensitivity of tumor towards chemotherapy and radiotherapy. The research and development of inhibitors of c-Met have become a hot spot in studies of antitumor field.
WO 2009/099982 A1 discloses 2-aminopyridine compound having the following structure:

and regards that these compounds are inhibitors of tyrosine kinase (KDR, Tie-2, Flt3, FGFR3, Ab1, AuroraA, c-Src, IGF-IR, ALK, c-Met, RON, PAK1, PAK2, TAK1, etc.) that can be used to treat diseases mediated by protein kinase activities, and further discloses the following structure:

WO 2008/008539 A2 discloses a series of fused heterocyclic derivates having the following structure:
and regards that these compounds are inhibitors of c-Met.
WO 2008/071451 A1 discloses dihydropyridine derivatives having the following structure:
and indicates that these compounds have inhibitory activities on protein tyrosine kinase and can be used to treat c-Met mediated diseases.
US 2007/0265272 A1 discloses a compound having the following structure:
which is used to treat or prevent c-Met related diseases in mammals and treat proliferative diseases.
Among the therapeutic methods using c-Met as the target, some c-Met micromolecular kinase inhibitors have already entered the stage of clinical tests (Expert Opin. Ther. Patents, 2010, 20 (2): 159-177).
In summary, c-Met is the therapeutic target for tumor therapy with a promising development perspective. The efficient search of specific c-Met inhibitors with high potency and low toxicity has important clinical sense and application perspective, and has already become a hot spot in the current antitumor researches.